chr6-129059863-C-A

Position:

chr6-129059863-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000426.4(LAMA2):c.363C>A(p.Tyr121*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,601,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

LAMA2
NM_000426.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 1.70

Variant links:

Genes affected

LAMA2 (HGNC:6482): (laminin subunit alpha 2) Laminin, an extracellular protein, is a major component of the basement membrane. It is thought to mediate the attachment, migration, and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. It is composed of three subunits, alpha, beta, and gamma, which are bound to each other by disulfide bonds into a cross-shaped molecule. This gene encodes the alpha 2 chain, which constitutes one of the subunits of laminin 2 (merosin) and laminin 4 (s-merosin). Mutations in this gene have been identified as the cause of congenital merosin-deficient muscular dystrophy. Two transcript variants encoding different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

LAMA2 links:

LAMA2 (HGNC:):

LAMA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 6-129059863-C-A is Pathogenic according to our data. Variant chr6-129059863-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 551699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-129059863-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMA2	NM_000426.4 linkuse as main transcript	c.363C>A	p.Tyr121*	stop_gained	3/65	ENST00000421865.3	NP_000417.3
LAMA2	NM_001079823.2 linkuse as main transcript	c.363C>A	p.Tyr121*	stop_gained	3/64		NP_001073291.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMA2	ENST00000421865.3 linkuse as main transcript	c.363C>A	p.Tyr121*	stop_gained	3/65	5	NM_000426.4	ENSP00000400365.2		P24043

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251358

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1448792

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721714

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000273

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Merosin deficient congenital muscular dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 05, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 01, 2017	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2021	Nonsense variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 30301903, 31589614, 32266982, 18700894, 24611677) -

LAMA2-related muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 11, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 551699). This premature translational stop signal has been observed in individuals with congenital muscular dystrophy (PMID: 18700894, 24611677, 30055037, 30301903). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs535635043, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Tyr121*) in the LAMA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMA2 are known to be pathogenic (PMID: 18700894, 32904964). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.091

FATHMM_MKL

Uncertain

0.89

Vest4

0.91

GERP RS

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over